The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of b-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing b-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear b-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of b-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Sensory afferent fibers are an important component of motor nerves and compose the majority of axons in many nerves traditionally thought of as “pure” motor nerves. These sensory afferent fibers innervate special sensory end organs in muscle, including muscle spindles that respond to changes in muscle length and Golgi tendons that detect muscle tension. Both play a major role in proprioception, sensorimotor extremity control feedback, and force regulation. After peripheral nerve injury, there is histological and electrophysiological evidence that sensory afferents can reinnervate muscle, including muscle that was not the nerve's original target. Reinnervation can occur after different nerve injury and muscle models, including muscle graft, crush, and transection injuries, and occurs in a nonspecific manner, allowing for cross‐innervation to occur. Evidence of cross‐innervation includes the following: muscle spindle and Golgi tendon afferent‐receptor mismatch, vagal sensory fiber reinnervation of muscle, and cutaneous afferent reinnervation of muscle spindle or Golgi tendons. There are several notable clinical applications of sensory reinnervation and cross‐reinnervation of muscle, including restoration of optimal motor control after peripheral nerve repair, flap sensation, sensory protection of denervated muscle, neuroma treatment and prevention, and facilitation of prosthetic sensorimotor control. This review focuses on sensory nerve regeneration and reinnervation in muscle, and the clinical applications of this phenomena. Understanding the physiology and limitations of sensory nerve regeneration and reinnervation in muscle may ultimately facilitate improvement of its clinical applications.

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BACKGROUND: Patients with symptomatic Crohn’s disease who undergo abdominoperineal resection can experience impaired postoperative wound healing. This results in significant morbidity, burdensome dressing changes, and increased postoperative pain. When abdominoperineal resection is performed for oncological reasons, autologous flap reconstruction is occasionally performed to optimize wound healing and reconstruction outcomes. However, the role of flap reconstruction after abdominoperineal resection for Crohn’s disease has not been established. OBJECTIVE: This study examines the utility of flap reconstruction in patients with symptomatic Crohn’s disease undergoing abdominoperineal resection. We hypothesize that patients with immediate flap reconstruction after abdominoperineal resection will demonstrate improved wound healing. DESIGN: This study is a retrospective chart review. SETTINGS: Eligible patients at our institution were identified from 2010 to 2018 by using a combination of Current Procedural Terminology, International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision codes. PATIENTS: Of 40 adult patients diagnosed with Crohn’s disease, 20 underwent abdominoperineal resection only and 20 underwent abdominoperineal resection with flap reconstruction. INTERVENTION(S): Immediate autologous flap reconstruction was performed after abdominoperineal resection. MAIN OUTCOME MEASURES: The primary outcomes measured were the presence of postoperative perineal wounds and postoperative wound care burden. RESULTS: Patients in the abdominoperineal resection with flap reconstruction group demonstrated significantly worse preoperative disease traits, including fistula burden, than patients in the abdominoperineal resection only group. A lower number of patients tended to be associated with a persistent perineal wound in the flap group at 30 days (abdominoperineal resection with flap reconstruction = 55% vs abdominoperineal resection only = 70%; p = 0.327) and at 6 months (abdominoperineal resection with flap reconstruction = 25% vs abdominoperineal resection only = 40%; p = 0.311) postoperatively. There was also a trend toward a lower incidence of complications in the flap group. Patients in the abdominoperineal resection with flap reconstruction group tended to experience lower postoperative pain than patients in the abdominoperineal resection only group. LIMITATIONS: This retrospective cohort study was limited by its reliance on data in electronic medical records, and by its small sample size and the fact that it was a single-institution study. CONCLUSIONS: In select patients who have severe perianal fistulizing Crohn’s disease, there may be a benefit to immediate flap reconstruction after abdominoperineal resection to lower postoperative wound care burden without significant intraoperative or postoperative risk. In addition, flap reconstruction may lead to lower postoperative pain. See Video Abstract at http://links.lww.com/DCR/B416. EL ROL DE LA RECONSTRUCCIÓN CON COLGAJO AUTÓLOGO EN PACIENTES CON ENFERMEDAD DE CROHN SOMETIDOS A RESECCIÓN ABDOMINOPERINEAL ANTECEDENTES: Los pacientes con enfermedad de Crohn sintomática que se someten a una resección abdominoperineal pueden experimentar una curación posoperatoria deficiente de la herida. Esto da como resultado una morbilidad significativa, cambios de apósito molestos y un aumento del dolor posoperatorio. Cuando se realiza una resección abdominoperineal por razones oncológicas, ocasionalmente se realiza una reconstrucción con colgajo autólogo para optimizar los resultados de la curación y reconstrucción de la herida. Sin embargo, no se ha establecido la función de la reconstrucción con colgajo después de la resección abdominoperineal para la enfermedad de Crohn. OBJETIVO: Este estudio examina la utilidad de la reconstrucción con colgajo en pacientes con enfermedad de Crohn sintomática sometidos a resección abdominoperineal. Presumimos que los pacientes con reconstrucción inmediata con colgajo después de la resección abdominoperineal demostrarán una mejor curación de la herida. DISEÑO: Revisión retrospectiva de expedientes. MARCO: Los pacientes elegibles en nuestra institución se identificaron entre 2010 y 2018 mediante una combinación de los códigos de Terminología actual de procedimientos, Clasificación internacional de enfermedades 9 y Clasificación internacional de enfermedades 10. PACIENTES: Cuarenta pacientes adultos diagnosticados con enfermedad de Crohn que se someten a resección abdominoperineal solamente (APR-solo = 20) y resección abdominoperineal con reconstrucción con colgajo (APR-colgajo = 20). INTERVENCIÓN (ES): Reconstrucción inmediata con colgajo autólogo después de la resección abdominoperineal. MEDIDAS DE RESULTADOS PRINCIPALES: Presencia de herida perineal posoperatoria y carga de cuidado de la herida posoperatoria. RESULTADOS: Los pacientes del grupo APR-colgajo demostraron rasgos de enfermedad preoperatoria significativamente peores, incluida la carga de la fístula, en comparación con los pacientes del grupo APR-solo. Un número menor de pacientes tendió a asociarse con una herida perineal persistente en el grupo de colgajo a los 30 días (APR-colgajo = 55% vs APR-solo = 70%; p = 0.327) y 6 meses (APR-colgajo = 25% vs APR-solo = 40%; p = 0.311) postoperatoriamente. También hubo una tendencia hacia una menor incidencia de complicaciones en el grupo APR-colgajo. Los pacientes del grupo APR-colgajo tendieron a experimentar menos dolor posoperatorio en comparación con el grupo APR-solo. LIMITACIONES: Estudio de cohorte retrospectivo basado en datos de historias clínicas electrónicas. Tamaño de muestra pequeño y estudio de una sola institución. CONCLUSIONES: En pacientes seleccionados que tienen enfermedad de Crohn fistulizante perianal grave, la reconstrucción inmediata del colgajo después de la resección abdominoperineal puede beneficiar a reducir la carga posoperatoria del cuidado de la herida sin riesgo intraoperatorio o posoperatorio significativo. Además, la reconstrucción con colgajo puede resultar un dolor posoperatorio menor. Consulte Video Resumen en http://links.lww.com/DCR/B416.